How does Zolgensma work? Unpacking the Gene Replacement Therapy for SMA

October 18, 2025 •

5 min read

In untreated cases, Spinal Muscular Atrophy (SMA) type 1, the most common and severe form, results in a low survival rate beyond the age of two. Zolgensma, a groundbreaking gene replacement therapy, works by delivering a healthy copy of the SMN1 gene to treat the underlying genetic cause of this devastating disease.

Quick Summary

Zolgensma is a gene therapy using a harmless adeno-associated virus (AAV9) vector to deliver a functional SMN1 gene to motor neurons. This allows for continuous production of the vital SMN protein, halting SMA progression with a single infusion.

Key Points

Gene Replacement Therapy: Zolgensma is a one-time gene therapy designed to replace the faulty or missing SMN1 gene that causes Spinal Muscular Atrophy (SMA).
AAV9 Viral Vector: A harmless virus called adeno-associated virus, serotype 9 (AAV9), is used as a delivery vehicle to carry the functional SMN1 gene into the patient's cells.
Blood-Brain Barrier Access: The AAV9 vector is uniquely able to cross the blood-brain barrier, allowing it to deliver the new gene directly to motor neurons in the central nervous system.
Restored SMN Protein Production: The delivered gene enables motor neurons to produce sufficient amounts of the essential Survival Motor Neuron (SMN) protein, halting the progression of the disease.
Critical Timing: Because the therapy cannot reverse irreversible motor neuron damage, it is most effective when administered early in an infant's life, ideally before symptom onset.
Mandatory Monitoring: Due to the risk of serious side effects like liver toxicity, patients receive corticosteroids and undergo extensive monitoring with blood tests for at least three months post-infusion.

The Genetic Root of Spinal Muscular Atrophy (SMA)

To understand how Zolgensma works, one must first grasp the genetic basis of Spinal Muscular Atrophy (SMA). This devastating neuromuscular disease is caused by a missing or mutated survival motor neuron 1 (SMN1) gene. The SMN1 gene is responsible for producing a protein called Survival Motor Neuron (SMN) protein, which is critical for the function and survival of motor neurons. Motor neurons are the nerve cells in the brainstem and spinal cord that control muscle movement. Without sufficient amounts of functional SMN protein, these motor neurons progressively lose their function and die, leading to muscle weakness, paralysis, and in severe cases, respiratory failure.

While humans also possess a backup gene called SMN2, this gene only produces a small fraction (about 10%) of the full-length, functional SMN protein needed to support motor neurons. The severity of SMA is often correlated with the number of SMN2 gene copies a person has, as more copies can lead to slightly more protein production. However, even with multiple copies, the amount of functional SMN protein is typically insufficient to prevent the disease's progression.

How does Zolgensma work? A gene replacement therapy

Zolgensma (onasemnogene abeparvovec) is a revolutionary gene therapy designed to address the root genetic cause of SMA. Instead of treating symptoms, it aims to replace the faulty or missing SMN1 gene with a new, functional copy. This is a one-time intravenous infusion that delivers the therapeutic gene directly to the patient's cells.

The treatment consists of two main components:

The therapeutic gene: A fully functional copy of the human SMN1 gene, which provides the correct genetic instructions for producing the vital SMN protein.
The delivery vehicle (vector): A modified, harmless virus that acts as a "delivery truck" to transport the new SMN1 gene into the patient's motor neuron cells.

The AAV9 Vector: A Viral "Delivery Truck"

The vector used in Zolgensma is a modified adeno-associated virus, specifically serotype 9 (AAV9). AAVs are a common choice for gene therapies because they are not known to cause disease in humans, making them generally safe. Furthermore, the AAV9 serotype was specifically chosen for its unique ability to cross the blood-brain barrier. This crucial property allows the vector to reach motor neuron cells throughout the central nervous system (CNS), including the brainstem and spinal cord, where the SMN protein is most needed.

To create the therapeutic vector, the viral DNA that would normally allow the virus to replicate is removed and replaced with the functional SMN1 gene. This prevents the vector from replicating or causing an infection, ensuring that it only serves its purpose as a delivery vehicle.

The Delivery and Transcription Process

The entire treatment is administered as a single, one-hour intravenous infusion. Once in the bloodstream, the AAV9 vectors travel throughout the body, eventually crossing into the CNS to reach the motor neurons.

Here is a step-by-step breakdown of the cellular process:

Vector Entry: The AAV9 vector attaches to and enters the motor neuron cells.
Gene Release: Once inside the cell's nucleus, the vector releases the functional SMN1 gene.
Episome Formation: The genetic elements of Zolgensma have been engineered to form a circular, double-stranded DNA structure called an episome within the cell's nucleus. Since motor neurons are non-dividing cells, this episome can persist for an extended period.
Continuous Protein Production: A promoter region within the episome enables the cell's own machinery to begin rapidly and continuously producing the SMN protein.

This restored production of SMN protein helps preserve the motor neurons, thereby halting or slowing the progression of SMA. It is important to note that because the treatment cannot reverse existing motor neuron loss, early intervention is critical for achieving the best possible outcomes.

Zolgensma vs. Other SMA Treatments

Zolgensma represents one of several significant treatment options available for SMA. Two other prominent therapies are Spinraza (nusinersen) and Evrysdi (risdiplam). A comparison highlights their distinct mechanisms and administration methods.


Feature	Zolgensma (Onasemnogene Abeparvovec)	Spinraza (Nusinersen)	Evrysdi (Risdiplam)
Mechanism	Gene replacement. Delivers a new, working copy of the SMN1 gene.	Antisense oligonucleotide. Modifies the splicing of the SMN2 gene to increase production of full-length SMN protein.	Small molecule. Modifies the splicing of the SMN2 gene to increase production of full-length SMN protein.
Administration	Single intravenous (IV) infusion.	Intrathecal injection (into the spinal fluid).	Oral solution, taken daily.
Frequency	One-time treatment.	Requires multiple loading doses followed by maintenance doses every four months.	Daily.
Target	Primarily replaces the missing SMN1 gene.	Targets the SMN2 gene.	Targets the SMN2 gene.

Safety Profile and Monitoring

While a powerful treatment, Zolgensma requires careful safety considerations and extensive monitoring due to potential side effects.

Potential Side Effects

Elevated Liver Enzymes and Liver Toxicity: This is a serious risk, and cases of acute liver failure have been reported. Patients with pre-existing liver impairment may be at higher risk. To mitigate this, patients receive a systemic corticosteroid (such as prednisone) before and after the infusion.
Thrombocytopenia: Transient decreases in platelet counts, which can increase the risk of bruising or bleeding, are often observed within the first two weeks following treatment.
Thrombotic Microangiopathy (TMA): This rare but serious condition involves the formation of blood clots in small blood vessels and has been reported in the post-marketing setting.
Increased Troponin-I Levels: Elevations in this cardiac enzyme, which may indicate damage to the heart muscle, have been observed, requiring cardiac monitoring.
Infusion-Related Reactions: Signs like rash, hives, or vomiting can occur during or after the infusion.

Monitoring Procedures

To ensure patient safety, a strict monitoring schedule is followed.

Before Infusion: Baseline lab tests are conducted, including liver function, complete blood count (including platelets), creatinine, and troponin-I levels. Testing for pre-existing anti-AAV9 antibodies is also performed, as high levels can make the therapy ineffective.
During and Immediately After Infusion: The patient is closely observed for any infusion-related reactions.
Post-Infusion Monitoring: For at least three months, the patient undergoes regular blood tests to monitor liver function (weekly for the first month, then every other week), platelet counts, and troponin-I levels.
Corticosteroid Management: The patient receives a daily corticosteroid regimen, starting the day before the infusion and continuing for at least 90 days afterward. The dose is carefully managed and tapered based on the monitoring results.

The Promise of Early Treatment

Clinical trials have demonstrated the immense potential of Zolgensma, particularly when administered early in the disease course. In studies involving infants with SMA type 1, treatment before significant symptoms appeared led to impressive motor function improvements, with some infants reaching motor milestones typically unachievable for untreated patients. Benefits observed include increased survival rates, reduced need for permanent ventilation, and improvements in motor skills such as head control, sitting unsupported, and even walking.

Conclusion

Zolgensma's mechanism, which directly addresses the genetic cause of Spinal Muscular Atrophy, represents a paradigm shift in the treatment of rare genetic diseases. By utilizing a harmless AAV9 viral vector to deliver a functional SMN1 gene, it restores the production of the essential SMN protein in motor neurons. The therapy offers a life-altering, one-time treatment option, but its use requires careful clinical management, emphasizing the critical importance of early diagnosis and rigorous post-infusion monitoring. Its development underscores the growing promise of gene replacement therapy in transforming the lives of patients with genetic disorders.

Gene Therapy for Spinal Muscular Atrophy (SMA): A Review of Onasemnogene Abeparvovec

Frequently Asked Questions

SMA is a rare genetic disease caused by a defect in the SMN1 gene, which leads to a deficiency of the SMN protein. This protein is essential for the health of motor neurons, and its lack causes progressive muscle weakness and wasting.

The new, functional SMN1 gene is delivered by a vector, which is a modified version of a harmless adeno-associated virus (AAV9). The AAV9 vector acts like a delivery vehicle, bringing the genetic material to the target cells.

Zolgensma is not considered a cure because it does not reverse motor neuron damage that has already occurred. However, it addresses the genetic root cause of SMA and can stop the disease's progression, especially when administered early.

No, the new gene delivered by the Zolgensma vector does not integrate into the child's chromosomes or DNA. It remains in the nucleus as a separate circular piece of DNA called an episome.

The most common side effects are elevated liver enzymes and vomiting. More serious, though less common, side effects include liver failure, heart problems, and blood clotting issues.

Patients are given corticosteroids before and for at least 90 days after the Zolgensma infusion to help prevent and manage potential inflammation of the liver, which is a serious side effect.

Zolgensma is a one-time gene replacement therapy that delivers a functional SMN1 gene. In contrast, Spinraza is an ongoing treatment that modifies the SMN2 backup gene to increase SMN protein production. They also differ in administration, with Zolgensma as an IV infusion and Spinraza as an intrathecal injection.

Regulatory approvals typically restrict Zolgensma to pediatric patients under a certain age (often under 2 years) due to its efficacy and safety profile in that population. However, clinical trials have explored its use in older and heavier children, with positive results reported.